This study is available free. Just click on this link to download it.
As a way of background, this is the second Phase 3 study for ISTURISA (osilodrostat). The first phase 3 study, LINC 3, published in Lancet in July 2020, demonstrated that ISTURISA enables some patients with Cushing’s disease to control their cortisol levels rapidly. Across Phase 2 and Phase 3 clinical trials, ISTURISA has been studied in over 200 people with Cushing’s disease.
“These results show that osilodrostat is an effective treatment for Cushing’s disease,” said Peter J. Snyder MD, Professor of Medicine at the University of Pennsylvania. “Osilodrostat rapidly lowered cortisol excretion to normal in most patients with Cushing’s disease and maintained normal levels throughout the 48-week core phase of the study. Importantly, this normalization was accompanied by improvements in cardiovascular and metabolic parameters, which decreases morbidity and mortality in Cushing’s disease.”
The LINC 4 study confirmed the efficacy (effectiveness) and safety of ISTURISA in patients with Cushing’s disease providing rapid and sustained control of cortisol levels in most patients during the 48-week core phase of the study. ISTURISA, an oral therapy, is very well tolerated by patients, according to the release. LINC 4 augments and confirms the results from the initial LINC 3 study. Click on this link to read the complete press release. In this phase of the study, 48 patients received ISTURISA, and 25 received a placebo for the first 12 weeks, followed by an open-label period during which all patients received ISTURISA until week 48; after that, patients could enter an optional extension phase.
The findings published in JCEM show many positive results. Here are a few highlights:
- LINC 4 met the primary endpoint (the most important outcome used to assess the primary objective of a trial), which was to show that ISTURISA was significantly superior to placebo at normalizing cortisol. The unit measured is mean urinary free cortisol (mUFC) at the end of a 12-week randomized, double-blind period.
- Effects of ISTURISA were rapid. Over one-quarter of patients taking ISTURISA achieved normal mUFC as early week 2 and 58% achieved control by week 5.
- The key secondary outcome was also met, with 81% of all patients in the study having normal mUFC at week 36.
- Improvements in cardiovascular and other clinical signs of Cushing’s disease, including blood pressure and blood glucose metabolism, were seen by week 12 and were maintained throughout the study.
- Hypercortisolism’s physical features improved during ISTURISA treatment, including fat pads, facial rubor, striae, and muscle wasting. Improvements were observed by week 12, with continued improvement throughout the study to week 48.
- Patient-reported quality of life (QoL) scores (CushingQoL and Beck Depression Inventory) also improved during ISTURISA treatment.
Importantly, ISTURISA was well tolerated in most patients, with no unexpected adverse events (AEs). The most common AEs overall were decreased appetite, arthralgia, fatigue, and nausea.
“The most significant need regarding the medical treatment of Cushing’s disease is a therapy that is highly effective and sustains cortisol normalization to relieve patients from the burden of co-morbidities and symptoms,” said William Ludlam, MD, PhD, Recordati’s chief medical officer. “The two phase 3 clinical trials (LINC 3 and LINC 4) have demonstrated that osilodrostat is an effective treatment for Cushing’s disease in the majority of patients.”
“These compelling data build on the positive Phase III LINC 3 study, published in The Lancet Diabetes & Endocrinology in 2020, demonstrating that ISTURISA enables most patients with Cushing’s disease to gain rapid control of their cortisol levels, which in turn provides relief from a host of undesirable symptoms,” said Alberto Pedroncelli, clinical development and medical affairs lead, global endocrinology of Recordati AG. “Recordati Rare Diseases is committed to improving the lives of patients with this rare, debilitating, and life-threatening condition. We would like to thank everyone who has contributed to the ongoing LINC clinical program.”
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